Project Summary/Abstract ? Project 1 Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non- small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. In efforts to improve upon this figure, the field has launched over 800 clinical trials (across all cancer types) testing novel therapeutics in conjunction with immune checkpoint blockade. Effectively none of these trials adequately address the neutrophil lineage as a substantial contributor to ICI treatment failure. We provide preliminary data that neutrophils are the most prevalent immune cell type in NSCLC, inversely correlate with CD8 cellular content, and preclude the presence of the IFN? signature, previously shown to correlate with favorable ICI treatment response. We will perform multiplex-immunohistochemistry on a dataset of FFPE slides obtained from patients treated with anti-PD1/PDL1 therapy to show that neutrophils associate with poor outcomes. We utilize a novel mouse model in which the tumor harbors hundreds of mutations to identify the mechanistic determinants of ICI treatment response and test a novel CXCR1/CXCR2 antagonist to synergize with anti-PDL1 treatment. Lastly, we will perform a Phase 2 clinical trial testing the combination of the novel CXCR1/CXCR2 antagonist (SX-682, Syntrix Biosystems, Inc.) and nivolumab in advanced stage NSCLC patients who have previously failed anti- PD1/PDL1 therapy.